INTRODUCTION — Fabry disease (also called angiokeratoma corporis diffusum, ceramide trihexosidosis, and Anderson-Fabry disease) is an X-linked glycolipid storage disease. It is caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, which causes progressive accumulation of alpha-D-galactosyl moieties, such as globotriaosylceramide (the glycolipid substrate for alpha-galactosidase A), within multiple cell types and tissues of affected patients [1]. Numerous mutations have been found in the alpha-galactosidase A gene (GLA gene) on the long arm of the X chromosome (Xq22).
This topic will review the neurologic manifestations of Fabry disease and their treatment.
Other clinical aspects of Fabry disease are presented elsewhere. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Treatment and prognosis" and "Fabry disease: Cardiovascular disease".)
OVERVIEW — Clinical manifestations of Fabry disease usually become evident by 10 years of age in the severe classic form. Initial manifestations typically include neuropathic pain (acroparesthesia), hypohidrosis, poor exercise tolerance, and fever of unknown origin. The characteristic skin lesions known as angiokeratomas develop in the second decade of life. By of the third decade of life, cardiovascular and renal disease become increasingly prominent [2]. An overview of the clinical manifestations of Fabry disease and other related disorders is presented in the table (table 1).
Progressive accumulation of globotriaosylceramide within endothelial, perithelial, and smooth muscle cells of the vascular system, dorsal root ganglia, and cells of the autonomic nervous system, result in the neurologic manifestations of the disease [3]. These include a small-fiber peripheral neuropathy and an increased propensity for ischemic stroke in affected males and female heterozygotes.
SMALL-FIBER PERIPHERAL NEUROPATHY — The length-dependent small-fiber peripheral neuropathy associated with Fabry disease may cause an almost constant discomfort of the hands and feet, with paroxysmal burning pains of the palms and soles [4,5]. Alternatively, it may cause recurrent painful episodes triggered by stress, fever, heat, fatigue, joint pain, or exercise [6]. The pain is sometimes misconstrued as "growth pain." Although pain tends to diminish with age secondary to progressive nerve fiber loss, it may be of sufficient severity to lead to suicide attempts.
Patients have decreased cold and warm perception that first manifests in the feet associated with decreased epidermal nerve fiber density in the affected regions [7,8]. Electron microscopy of peripheral nerves reveals loss of unmyelinated and small myelinated nerve fibers and lamellar inclusions in the perineurium and the dorsal root ganglia likely consisting of glycosphingolipids [9,10]. Nerve conduction studies are consequently normal [7,8]. A study employing functional magnetic resonance neurography found that patients with Fabry disease had symmetrically enlarged dorsal root ganglia with decreased permeability of the blood-tissue interface, the latter consistent with dysfunctional perfusion [11].
Pain relief — The treatment of chronic neuropathic pain in patients with Fabry disease remains empiric [12]. Preventive pain therapy with gabapentin, carbamazepine, and amitriptyline appears to be beneficial [13]. All three are approved by the US Food and Drug Administration (FDA) for the treatment of neuropathic pain.
One potential advantage of anticonvulsants is that compliance may be monitored and the risk of toxicity reduced by following serum levels. However, these levels do not have a direct correlation with neuropathic pain response.
Narcotic agents should be avoided if possible. Nonsteroidal anti-inflammatory agents should also be avoided, as these tend to be ineffective and may lead to renal toxicity.
Gabapentin and pregabalin — Gabapentin and pregabalin bind to the voltage-gated calcium channels at the alpha 2-delta subunit and inhibit neurotransmitter release. They have efficacy versus placebo in several neuropathic pain conditions. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Antiseizure medications'.)
Advantages of gabapentin and pregabalin include low toxicity, a low incidence of drug interactions, and lack of liver metabolism.
In children less than 12 years old, the starting dose of gabapentin is 10 to 15 mg/kg per day divided into three doses. The dose may be slowly increased up to 50 mg/kg daily. For older children and adults the initial dose is typically 300 mg three times per day (900 mg total per day). The maximum total dose may be in the range of 1800 to 2400 mg per day.
One advantage of pregabalin is twice daily dosing compared with three time daily dosing for gabapentin. Pregabalin is usually started at a dose of 75 mg twice daily; the dose may be increased by the same amount after four to seven days to a typical total daily dose of 300 mg or to a maximum total daily dose of 600 mg as necessary and tolerated [14].
Both gabapentin and pregabalin can produce dose-dependent dizziness and sedation that can be reduced by starting with lower doses and titrating slowly.
The nearly complete renal clearance for gabapentin and pregabalin is potentially concerning in patients with Fabry disease, who are at risk for kidney disease. Therefore, renal function should be assessed before beginning gabapentin treatment and the dose should be adjusted accordingly, as renal function affects serum levels and half-life.
Other anticonvulsants — A number of other anticonvulsants have been used for the treatment of neuropathic pain. Of the older drugs, carbamazepine and phenytoin have been used most often [15,16]. However, phenytoin is not commonly used for chronic treatment in children because of concerns about adverse cosmetic effects that include hirsutism, gingival hyperplasia and coarse facial features. In addition, chronic phenytoin treatment has been associated with the potential for cerebellar atrophy and peripheral neuropathy. Carbamazepine appears to be effective but causes induction of the P450 system in the liver, which can be a concern in patients on multiple drugs that are metabolized by the liver.
Amitriptyline — Amitriptyline, at doses well below those used in the treatment of depression, has been shown to be effective in the treatment of chronic neuropathic pain [17]. At the lower doses used for neuropathic pain, serious side effects are uncommon. Nonetheless, an electrocardiogram should be obtained before and after beginning treatment since amitriptyline can cause adverse changes in cardiac conduction.
The recommended starting dose of amitriptyline in children is 0.1 mg/kg at night. This can be slowly increased over two to four weeks up to 0.5 to 2 mg/kg nightly.
CEREBROVASCULAR COMPLICATIONS — Cerebral involvement in Fabry disease is due mainly to vasculopathy and a dilative arteriopathy in affected males and female carriers and may result in transient ischemic attack and almost always ischemic stroke. There is evidence of a resting cerebrovascular hyperperfusion in males with Fabry disease, which may cause increased shear stress and vessel wall damage over time [18]. The manifestations of stroke in Fabry disease are no different from ischemic stroke due to other common etiologies, and any stroke-related clinical deficit might occur. White matter abnormalities, seen best on fluid-attenuated inversion recovery (FLAIR) MRI images, are asymptomatic or related to subtle neuropsychological deficits [19-24]. Cerebrovascular complications are rare in children, but increase through adult life.
In data from 2446 patients in the observational Fabry Registry, the following results were reported [25]:
●Stroke affected 138 patients (6 percent), including 86 of 1243 males (7 percent) and 52 of 1203 females (4 percent). Most strokes were ischemic (87 percent).
●Median age at first stroke for males and females was 39 and 45.7 years, respectively.
●The proportion of patients with a first stroke prior to the diagnosis of Fabry disease in males and females was 50 and 38 percent, respectively. The proportion who experienced a stroke prior to renal or cardiac events for males and females was 71 and 77 percent.
From these data, the risk of stroke in male subjects 35 to 45 years of age with the classic form of Fabry disease is approximately 12-fold higher compared with the general population of similar age. In addition, stroke often occurs before the renal or cardiac manifestations of Fabry disease.
In an earlier literature review, the average age of onset for cerebrovascular symptoms of Fabry disease was 34 years for hemizygotes (n = 43) and 40 years for heterozygotes (n = 10) [21]. The most frequent cerebrovascular manifestations in hemizygotes were hemiparesis, vertigo, dizziness, diplopia, dysarthria, nystagmus, nausea, vomiting, head pain, hemiataxia, and ataxia of gait. Heterozygotes were prone to memory loss, dizziness, ataxia, hemiparesis, loss of consciousness, and hemisensory symptoms. The most common angiographic and pathologic features were elongation, ectasia, and tortuosity involving the vertebral and basilar arteries.
The cerebrovascular disease burden, in particular the white matter lesion load, increases with age. In a longitudinal study of 149 patients with Fabry disease, with a mean follow-up of seven years, factors associated with MRI progression of white matter lesions and cerebral infarctions were age and male sex [26]. In another MRI study, lesions were present in no male patient under age 26 compared with all patients over age 54 [27]. Of the patients with white matter lesions, neurologic symptoms were present in 37.5 percent.
White matter lesions also appear over time in female carriers. The Fabry Outcome Survey found that cerebrovascular events occurred in a high proportion of female and male patients (27 versus 12 percent) [28,29]. The mean age of cerebrovascular event onset was below 30 years in men and below 45 years in women. In a subsequent case series of patients with symptomatic Fabry disease, the frequency of marked white matter lesions was similar among male and female patients (4 of 13 versus 5 of 14 [31 versus 36 percent]) [30].
The high burden of white matter lesions and cerebrovascular events in women with Fabry disease (an X-linked disorder) may be explained by the lack of cross-correction from enzyme-replete to enzyme-deficient cells in females [31]. The risk of stroke is, in part, related to the ratio of mutated to normal cells in the vascular system resulting from random X-inactivation occurring in early development [32].
STROKE PREVENTION — Standard ischemic stroke prevention measures are considered effective in secondary (and possibly primary) prevention for patients with Fabry disease, although this conclusion is based solely upon clinical experience [33].
These measures include the use of antiplatelet agents and, in particular, clopidogrel. In our clinical experience, stroke recurrence is frequent in patients with Fabry disease who are treated with aspirin. Therefore, for primary (in adult males with the classic form of the disease and a family history of stroke) and secondary stroke prevention, we suggest clopidogrel 75 mg once daily rather than aspirin. The combination drug aspirin-extended-release dipyridamole may be useful. Antihypertensive agents and statins are often used. These treatments are discussed in detail separately. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Overview of secondary prevention of ischemic stroke".)
FABRY-SPECIFIC THERAPY — Available Fabry-specific treatments include enzyme replacement therapy (agalsidase alfa and agalsidase beta) and pharmacologic chaperone therapy (migalastat). The effect of these interventions for the various manifestations of Fabry disease, including neuropathic pain symptoms and risk of ischemic stroke, is reviewed elsewhere. (See "Fabry disease: Treatment and prognosis".)
REGISTRY — A Fabry disease registry has been established to better understand the disease. Information is available online at https://www.registrynxt.com/. Participation in the registry is voluntary.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fabry disease".)
SUMMARY AND RECOMMENDATIONS
●Peripheral neuropathy associated with Fabry disease causes an almost constant discomfort with paroxysmal burning pains of the hands and feet. (See 'Small-fiber peripheral neuropathy' above.)
●Prophylactic therapy for neuropathic pain with gabapentin, carbamazepine, phenytoin, or amitriptyline may provide relief. (See 'Pain relief' above.)
●Cerebral involvement in Fabry disease is due mainly to vasculopathy and a dilative arteriopathy in affected males and female carriers and may result in transient ischemic attack, stroke, aneurysms, acute blindness, and accumulation of symptomatic and asymptomatic white matter lesions. Cerebrovascular complications are rare in children, but increase through adult life. (See 'Cerebrovascular complications' above.)
●For primary (in adult males with the classic form of the disease and a family history of stroke) and secondary prevention of ischemic stroke in adults or children with Fabry disease, we suggest antiplatelet therapy with clopidogrel (75 mg daily) rather than aspirin (Grade 2C). Antihypertensive agents and statins may be used as appropriate. (See 'Stroke prevention' above.)
●Fabry-specific treatments, including enzyme replacement therapy (agalsidase alfa and agalsidase beta) and pharmacologic chaperone therapy (migalastat), are discussed elsewhere. (See "Fabry disease: Treatment and prognosis".)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Robert Cruse, DO, and Raphael Schiffman, MD, MHSc, FAAN, who contributed to an earlier version of this topic review.
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